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Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy

Fabian Braun1,2, Ahmed Abed3, Dominik Sellung3

  • 1III. Department of Medicine and.

The Journal of Clinical Investigation
|April 4, 2023
PubMed

Insights

Current Fabry disease therapies reduce globotriaosylceramide (Gb3) but don't reverse kidney damage. This study reveals alpha-synuclein (SNCA) accumulation drives podocyte injury, suggesting SNCA modulation as a novel therapeutic target for Fabry nephropathy.

Area of Science:

  • Nephrology
  • Genetics
  • Cell Biology

Background:

  • Fabry disease therapies aim to reduce globotriaosylceramide (Gb3) accumulation and lysosomal dysfunction.
  • The efficacy of current treatments in reversing established end-organ damage, particularly kidney injury, is not fully understood.

Purpose of the Study:

  • To investigate the impact of enzyme replacement therapy (ERT) on podocyte injury in Fabry disease.
  • To identify novel mechanisms underlying podocyte injury beyond Gb3 accumulation.
  • To explore new therapeutic targets for Fabry nephropathy.

Main Methods:

  • Ultrastructural analysis of human kidney biopsies.
  • CRISPR/Cas9 gene editing to create α-galactosidase knockout podocytes.
  • Transcriptome-based connectivity mapping and SILAC-based quantitative proteomics.
  • Genetic and pharmacological inhibition of α-synuclein (SNCA).

Main Results:

  • Long-term ERT reduced Gb3 in podocytes but did not reverse podocyte injury or fully restore lysosomal function.
  • α-synuclein (SNCA) accumulation was identified as a key mediator of podocyte injury.
  • Inhibition of SNCA improved lysosomal structure and function in Fabry podocytes, surpassing ERT benefits.

Conclusions:

  • Fabry disease-associated podocyte injury involves mechanisms beyond Gb3 accumulation, notably SNCA accumulation.
  • Modulating SNCA presents a promising therapeutic strategy for Fabry nephropathy, potentially offering greater benefits than current ERT.
Keywords:
Chronic kidney diseaseDrug therapyGenetic diseasesGeneticsNephrology

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